17{62 -hydroxy-10,17{60 {62 -dimethyl-d-homo-c-nor-13{60 -gon-4-en-3-one and congeners

ABSTRACT

Preparation of 17 Beta -hydroxy-10,17 Alpha Beta -dimethyl-Dhomo-C-nor-13 Alpha -gon-4-en-3-one and congeners, and their capacity to block the effect of DCA on urinary sodium and potassium, are disclosed.

United States Patent Inventor Appl. No.

William F. Johns Glenview, lll.

Apr. 25, 1968 Nov. 23, 1971 G. D. Searle & Co.

Chicago, Ill.

Continuation-impart of application Ser. No. 545,582, Apr. 27, 1966, nowabandoned. This application Apr. 25, 1968, Ser. No. 724,249

l7B-HYDROXY-10,17aB-DIMETHYL-D-HOMO-C- NOR-l3a-GON-4-EN-3-ONE ANDCONGENERS 18 Claims, No Drawings 0.8. CI 260/586 H, 260/476 C, 260/488B, 260/999 Int. Cl ..C07c 49/30, C07c 49/48 Field of Search 260/586 H,

[56] References Cited UNITED STATES PATENTS 3,361.79l 1/1968 Johns etal. 260/476 OTHER REFERENCES Johns et al.. J. Org. Chem. Vol. 30, pp.l23- 13l (I965) Kupchan et al.. J. Am. Chem. Soc., Vol. 86, pp. 701- 708Primary Examiner-Bemard Helfin Assistant Examiner-Gerald A. SchwartzAttorneys-John M. Brown, John J. Kolano, Elliott Nv Schubert. Walter C.Ramm and Helmuth A. Wegner wherein R represents hydrogen or an alkylradical; Z represents a carbonyl or oxymethylene radical of the formulasC=0 and respectively, in which R represents hydrogen or an acyl radicaland R" represents hydrogen or an alkyl or alkynyl radical; and theendocyclic dotted lines designate the location of an optional doublebond in either, but not both, of rings A and B.

The alkyl radicals called for in the foregoing formulas are preferableof lower order, i.e., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, isohexyl, heptyl, andlike monovalent, saturated, acyclic, straightor branched-chain,hydrocarbon groupings of empirical formula n h-H wherein n is a positiveinteger less than 8. An especially preferred embodiment of R is methyl.

The alkynyl radicals contemplated by R" are likewise most desirably oflower order, i.e., groupings which can be thought of as derived frompolycarbon lower alkyl radicals by displacement of hydrogen to give riseto a triple bond. Illustrative lower alkynyl radicals are ethynyl,l-propynyl, Z-propynyl, lbutynyl, Z-butynyl, 3-butynyl, and the like,among which ethynyl is especially preferred.

The acyl radicals embraced by R are alkanoyl, benzoyl, and likeart-recognized pharmacologically-acceptable esterifying moieties amongwhich lower alkanoyl groupings -i.e., those having the formula alkyl andbenzoyl are preferred.

The compounds to which this invention relates are distinguished from theprior art by reason of their 13 alpha hydrogen and l7a beta/nor alkylstructure, and the valuable and totally unforeshadowed pharmacologicalutility which characterizes them. Specifically-like the well-knowndiuretic, spironolactone-the claimed compounds block the effect ofdesoxycorticosterone acetate (DCA) on urinary sodium and potassium.

The surprising anti-DCA activity of the compounds of this invention isshown by standardized tests for the aforesaid property carried outsubstantially as described in Ser. No. 647,600 filed June 21, I967,excepting that test compounds are administered subcutaneously instead oforally, and in sufficiently various dosage to enable determination ofthat does of each compound (the so-called median effective dosehereinafter abbreviated as MED) which produces a mean log NaXlO/K valueidentical to that produced by 0.33 mg. of spironolactone. Results ofsuch tests on representative compounds of the instant invention aretabulated below:

cue-3. l7-dionc' letartoacetonale Various prior art and othermore-or-less closely related compounds, when tested by the foregoingprocedure, afiorded results set forth in table ll:

TABLE ll Compound MED gona-l ,4-dien-3-one 2.4 l0,l7nB-dimethyl-D-homo-C-nor-Sa,l Bn-gonane 3, l 7-dione 2.4 l7a-hydroxyl0,1 73, l 7aa-trimethyl-D-homo-C-nordione 24lO-methyl-D-horho-C-nor-Sa,l Ja-D-homo-C-norgon-4-cn-3-one l .05

l7B-hydroxyl 0. l 7afl-dimethyl-D-homo-C-nor-gon-4- en-3-onetetartoacetonate 2.4

Preparation, but no biological properties, of the asterisked compoundsis disclosed in J. Org. Chem., 30, I23 (l965). Compounds which, at amaximum dose of 2.4 mg. failed to produce a mean log NaXlO/K value equalto or greater than the value produced by 0.33 mg. of spironolactone mayor may not have any anti-DCA activity; in either case, their potency wasinsufficient to warrant determination of MEDs.

From the foregoing results it appears, i.a., that the 1721/3- methylproduct of example 9 hereinafter blocked the urinary electrolyte effectsof DCA at less than one-seventh the dose at which the prior artl7aB-epimer did not. The l7aB-methyll 3 a product of example 14 blockedDCA at less than one thirtysixth the dose at which the l7aa-epimerproduced a comparable block, and less than one forty-sixth the dose atwhich the l3B-epimer did not. And the A product of example 15 blockedDCA at one-sixth the dose at which the saturated A ring analog did not.Potency of the product of example 14, relative to the spironolactonestandard, was 635 percent.

Compounds of the formula wherein R and Z are defined as before can beprepared from the corresponding SB-ols by oxidation with chromiumtrioxide in aqueous acetonic sulfuric acid (Jones reagent). Upon heatingwith selenium dioxide in tert-butyl alcohol and pyridine, compounds offormula ll afford the corresponding A" derivatives. The lattercompounds, in turn, afford the A analogs on contacting intetrahydrofuran solution with lithium and ammonium chloride in liquidammonia. From the A compounds, on heating with chloranil in ten-butylalcohol, the A- derivatives are obtained.

As a preferred alternative to the foregoing reaction sequence, compoundsof formula II and A A, and A derivatives thereof wherein a hydroxyl ispresent at carbon atom 17 are prepared from the corresponding l7-estersby saponification in hot aqueous methanolic potassium hydroxide.

An alternative preparation of l0, 1 7aB-dimethyl-D-homo-C-nor-l3a-gona-l,4-diene-3,17-dione involves fermentation of 3B-acetoxylO-methyl-D-homo-C-nor 5a, 1 3a-gonanl 7B-yl methyl ketone with theNorcardia sp. on deposit in the American Type Culture Collection underaccession number 19534, freely available on request.

An alternative preparation of the A-l7-oxy compounds of fonnula llproceeds by contacting the corresponding l,2,3,4- tetrahydro compoundswith 2 equivalents of bromine in acetic acid catalyzed by hydrogenbromide. The 2a,4a-dibromo derivatives which eventuate are heated withiodoacetone in an acetonic medium containing sodium iodide to give thecorresponding 2-iodo-4-en-3-ones. iodine is then replaced by hydrogen inthe latter compounds on contacting with zinc dust in acetic acid.

An alternative preparation of the A, A, and A--3,l7- diones of formulaII starts with the corresponding l7/3-ols, which yield the diones onoxidation with Jones reagent.

An alternative route to the A, A, and A" esters of formula II is theacylation of corresponding l7-ols by heating with an appropriate acidanhydride or halide in the presence of an acid acceptor such aspyridine.

The 3fl-ols required for preparation of the compounds of formula llwherein Z represents fi-alkanoyl-oxymethylene can be obtained bycontacting an appropriate ketone of the formula R H I III wherein R isdefined as before, with an appropriate (alkyl/alkynyl) magnesium halidein ethereal tetrahydrofuran and then diluting with water.

The foregoing and other representative procedures for preparingcompounds illustrative of the present invention are detailed in thefollowing examples. However, the invention is not to be construed aslimited thereby, either in spirit or in scope, since it will be apparentto those skilled in the art of organic synthesis that manymodifications, both of materials and of methods, may be practicedwithout departing from the purpose and intent of this disclosure.Throughout the examples hereinafter set forth, temperatures are given indegrees centigrade and relative amounts of materials in parts by weight,except as otherwise noted.

EXAMPLE l 10, l 7aB-Dimethyl-D-homo-C-nor-l 3a-gonal ,4-diene-3,17-dione. A sterile nutrient bacteriological medium consisting of 600parts of commercial beef extract, I000 parts of commercial peptone, and200,000 parts of distilled water is inoculated with 500 parts of aculture of Nocardia sp. A.T.C.C. no. 19534. The resultant mixture isincubated with agitation and aeration for 24 hours at approximately 25,whereupon a solution of I37 parts of 3fl-acetoxy-l0,l7aB-dimethyl-D-homo C-nor-5a,l3a-gonan-l7B-yl methyl ketone [.I. Org. Chem, 30, 123(1965)] in 3200 parts of acetone and 3200 parts of methanol isintroduced. Incubation as before is thereupon resumed for 40 hours. Themixture thus obtained is extracted with dichloromethane. Solvent isremoved from the extract by distillation; and the residue ischromatographed on CH; H CH3 EXAMPLE 2 A.10,17a,]7aB-Trimethyl-D-homo-Gnor-Sa,l 3a-gonane- 33,17fi-diol. To asolution of 357 parts of methyl-magnesium bromide in 4200 parts of etheris added a solution of 100 parts of 3B-hydroxy-10,17aB-dimethyl-D-homo-C-nor-5a,l 3agonan-l7-one [J. Org. Chem., 30,123 (1965)] in 1800 parts of tetrahydrofuran. The resultant solution isstirred at room temperatures for 20 hours, whereupon it is diluted with5 volumes of water followed by sufficient aqueous 5 percent hydrochloricacid to dissolve the salts. The resultant mixture is extracted withether. The ether extract is consecutively washed with water, aqueouspotassium bicarbonate, and water, then dried over magnesium sulfate andfreed of solvent by vacuum distillation. The residue is 10,1 701,17aB-trimethyl- D-homo-C-nor-5a,l 3a-gonane-3B, l 7B-diol which,recrystallized from a mixture of acetone and hexane, melts atapproximately l49-150.

B. 3,8,17B-Diacetoxy-1OJ7a,l7aB-trimethyl-D-hom0-C- nor-50:,l3a-gonane.To a solution of 10 parts of 10, l 70:, l 7aB-trimethyl-D-homo-C-nor-5a, l 3a-gonane-3 l 7B-diol in' a mixture of 200parts of acetic anhydride and l of toluenesulfonic acid is stirred atroom temperatures for 6 hours, then heated at for 2 hours. The solutionis then cooled and poured into 5 volumes of a mixture of equal parts ofaqueous 5 percent sodium bicarbonate and ice. The resultant mixture isextracted with dichloromethane. The extract is washed with aqueous 5percent potassium hydroxide and then stripped of solvents by vacuumdistillation. The residue is chromatographed on silica gel, usingbenzene and ethyl acetate as developing solvents. From an eluatecomprising 2 percent ethyl acetate in benzene, on evaporation of thesolvents, 3B,] 7B-diacetoxy-l0,l7a l 7aB-trimethyl-D-homo-C-nor-5a,l3a-gonane is obtained.

C. l 7B-Acetoxy-10,l 7a,l 7aB-trimethyl-D-homo-C-nor-5a,l3a-gonan-3/3-ol. To a solution of 1 part of 35,173-diacetoxy-l0,1701,17a,B-trimethyl-D-homo-C-nor-Sa,13agonane in l4 partsof methanol is added 2 parts of saturated aqueous potassium bicarbonateand 2 parts of water. The resultant mixture is heated at the boilingpoint for 2 hours, then cooled and extracted with dichloromethane. Theextract is washed with water and stripped of solvent by vacuumdistillation. The residue is chromatographed on silica gel, usingbenzene and ethyl acetate as developing solvents. From an eluatecomprising 5 percent ethyl acetate, on evaporation of solvents,7B-acetoxyl 0, 1 7a, 1 7aB-trimethyl-D-homo-C-nor- 501,1 3a-gonan-3B-olis obtained.

D. l 7B-Acetoxyl 0, 1 7a, 1 7aB-trimethyl-D-homo-C-nor- 5a,l3a-gonan-3-one. To a solution of 135 parts of 173- acetoxyl 0,17a,l7a/3-trimethyl-D-homo-C-nor-Sa,13agonan-3B-ol in 2400 parts ofacetone at 5 is added 27 parts of chromium trioxide in a mixture of 39parts of sulfuric acid and 150 parts of water. After 15 minutes, 3000parts of water and 160 parts of 2-propanol are introduced. The resultantmixture is extracted with benzene; and the benzene extract isconsecutively washed with water, aqueous 5 percent potassiumbicarbonate, and water. The extract is then dried over magnesium sulfateand stripped of solvent by vacuum distillation. The residue ischromatographed on silica gel, using benzene and ethyl acetate asdeveloping solvents. From an eluate comprising 3 percent ethyl acetatein benzene, on evaporation of solvents, l 7B-acetoxyl 0,17aB-trimethyl-D-homo-C-nor-5a ,l 3a-gonnan-3-one is obtained.

E. l 7B-Acetoxyl 0,] 701,1 7aB-trimethyl-D-homo-C-norl3a-gona-l,4-dien-3-one. A mixture of 33 parts of [7B- acetoxyl 0, l7aB-trimethyl-D-homo-C-nor-Sa,l 3a-gona-3- one, 20 parts of seleniumdioxide, parts of pyridine, and 1200 parts of tert-butyl alcohol isheated at the boiling point under reflux in a nitrogen atmosphere for 65hours. The resultant mixture is filtered, and the filtrate is extractedwith ethyl acetate. The extract is consecutively washed with water,aqueous l0 percent potassium bicarbonate, water, ice-cold aqueous l0percent ammonium sulfide, ice-cold 10 percent ammonium hydroxide, water,5 percent potassium bicarbonate, whereupon solvent is removed by vacuumdistillation and the residual oil chromatographed on silica gel, usingbenzene and ethyl acetate as developing solvents. From an eluatecomprising 5 percent ethyl acetate in benzene, upon evaporation of thesolvent and recrystallization of the residue from a mixture of acetoneand'hexane, l7B-acetoxy-l0,l7 01,1 7a/3l 3agona-l ,4-dien-3-one isobtained.

EXAMPLE 3l7B-Acetoxy-l0,l7a,l7afl-trimethyl-D-homo-C-nor-13agon-4-en-3-one. To amixture of 630 parts of liquid ammonia at -70 with 3 parts of lithium isadded 9 parts of l7B-acetoxyl0, 1 7a, 1 7aB-trimethyl-D-homo-C-nor-l3a-gona-l ,4-dien-3- one in 180 parts of tetrahydrofuran, followed 5minutes later by 200 parts of ammonium chloride. As soon as the bluecolor disappears, the ammonia is removed by distillation and the residuethereupon diluted with an equal volume of water. The resultant mixtureis extracted with dichloromethane. The extract is washed with water andstripped of solvent by vacuum distillation. The residue isl7B-acetoxy-l0,l7a,l7afltrimethyl-D-homo-C-nor-l 3a-gon-4-en-3-one,having the formula EXAMPLE 4 A.l7B-Hydroxy-1OJ7a,l7aB-trimethyl-D-homo-C-nor- 5a,13a-gonan-3-one. To asolution of parts of 10, l 701,17 aB-trimethyl-D-homo-C-nor-Sa, l3a-gonane-3B, l 7B-diol in 2400 parts of acetone at 5 is added 27 partsof chromium trioxide in a mixture of 39 parts of sulfuric acid and l50parts of water. After 15 minutes, 3000 parts of water and parts of2-propanol are introduced. The resultant mixture is ex tracted withether. The ether extract is consecutively washed with water and aqueous1 percent potassium bicarbonate, dried over magnesium sulfate, andstripped of solvent by vacuum distillation. The residue isrecrystallized from a mixture of ether and hexane to givel7B-hydroxy-l0,l7a,l7afitrimethyl-D-homo-C-nor-Sa,l3a-gonan-3-onemelting at approximately 128-129.

B. l7B-Hydroxy- I 0, 1 7a, 17aB-trimethyl-D-homo-C-norl3a-gona-l,4-dien-3-one. A mixture of 33 partsof 178- hydroxyl 0, 1 7a, l7aB-trimethyl-D-homo-C-nor-5a,l 3agonan-3-oneand 20 parts of selenium dioxide in a mixture of l200 parts oftert-butyl alcohol and I0 parts of pyridine is heated at the boilingpoint under reflux in a nitrogen atmosphere for 65 hours. The redprecipitate which forms is filtered off at the termination of theheating period and washed with ethyl acetate. Filtrate and wash are thencombined and concentrated to dryness by vacuum distillation. The residueis taken up in ethyl acetate. The ethyl acetate solution isconsecutively washed with water, aqueous 10 percent potassiumbicarbonate, water, ice-cold 10 percent ammonium sulfide, ice-cold l0percent ammonium hydroxide, water, The product CH VJ CH3 EXAMPLE 5 l7B-hydroxyl 0,1 701,1 7al3-trimethyl-D-homo-C-norl 30:- gon-4-en-3-one.Substitution of 630 parts of 17,8-hydroxy-l0, 1 701,17a-trimethyl-D-homo-C-nor-l 3a-gona-l ,4-dien-3-one for thel7B-trimethyl-D-homo-C-nor- 1 3a, 1 7aB-trimethyl-D-homo-C-nor-13a-gona-l ,4-dien-3-one called for in example 3 affords, bythe procedure there detailed, I7/3-hydroxy-l0,17 a, l 7aB l3a-gon-4-en-3-one which, recrystallized from hexane, melts atapproximately l35-l36. The product has the formula CH3 CH3 I /OH T'Qhm;

EXAMPLE 6 l 7 B-l-lydroxyl 0, 1 7a, 1 7aB-trimethyl-D-homo-C-norl 30:-gona-4,6-dien-3-one. To 60 parts of l7fi-hydroxy-l0,l7 :,1 7afil3a-gon-4-en-3-one in 78 parts of tert-butyl alcohol is added 100 partsof chloranil. The resultant mixture is stirred at the boiling pointunder reflux in a nitrogen atmosphere for hours. It is then cooled toroom temperature and diluted with 5 volumes of water. The mixture thusobtained is extracted with dichloromethane. The extract is successivelywashed with aqueous 5 percent potassium hydroxide and water, whereuponsolvent is removed by distillation and the residue chromatographed onsilica gel, using benzene and ethyl acetate as The resultant solvents.From an eluate comprising 5 percent ethyl acetate in benzene. onevaporation of solvent, l7B-hydroxy-l0,l7a,l7afl-trimethyl-D-homo-C-nor-l3a-gona-4,6-dien-3-one is obtained. The product has theformula EXAMPLE 7 A. l7a-Ethynyll 0, l 7aB-dimethyl-D-homo-C-nor-Sa, l30:- gonane-3fl,l 7fl-diol. To 360 parts of tetrahydrofuran containing40 parts of ethynylmagnesium bromide prepared as described in OrganicSynthesis, Coll. Vol. IV, page 792, is added, during minutes at 5. 2parts of 3B-hydroxy-l0,l7 aB-dlrnethyl-D-homo-C-nor-Sa, l 3a-gonanl7-one [J Org. Chem. 30, I23 (1965)] in 45 parts of tetrahydrofuran. Theresultant mixture is stirred at room temperatures for 2 hours. thenpoured into a solution of 20 parts of ammonium chloride in l000 parts ofwater. The resultant mixture is extracted with ether, and the etherextract is washed with water and thereupon stripped of solvent by vacuumdistillation. Recrystallization of the residue from a mixture of acetoneand hexane affords l 7a-ethynyll 0. l 7aB-dimethyl-D-homo-C-nor-Sa, IBetgonane-3B, l 7fi-diol.

B. l 7a-Ethynyll 7fl-hydroxyl 0, l 7a,8-dimethyl-D-homo-C-nor-5a,]3a-gonan-3-one. To a solution of 135 parts of I70!- ethynyll 0,l 7aB-dimetl'tyl-D-homo-C-nor-5d,] 3a-gonane-3 B,l7/3-diol in 2400 partsof acetone at 5 is added 27 parts of chromium trioxide in a mixture of39 parts of sulfuric acid and parts of water. After 5 minutes, 3000parts of water and parts of 2-propanol are introduced. The resultantmixture is extracted with benzene; and the benzene extract isconsecutively washed with water, aqueous 5 percent potassiumbicarbonate, and water. The extract is then dried over magnesium sulfateand stripped of solvent by vacuum distillation. Recrystallization of theresidue from a mixture of acetone and hexane affords l 7a-ethynyll7fl-hydroxyl 0, l 7B-dimethyl-D- homo-C-nor-Sa, l 3a-gonan-3-one meltingat l 76- l 78".

C. l 7a-Ethynyll 7B-hydroxyl 0, l 7afi-dimethyl-D-homo-C-nor-l3a-gona-l,4-dien-3-one. A mixture of 33 parts of 17aethynyll7B-hydroxyl 0, l 7afi-dimethyl-D-homo-C-nor-Sa, l 3 a-gonan-3-one and 20parts of selenium dioxide in a mixture of 1200 parts of tert-butylalcohol and 10 parts of pyridine is heated at the boiling point underreflux in a nitrogen atmosphere for 65 hours. The red precipitate whichforms is thereupon filtered off and washed with ethyl acetate. Filtrateand wash are combined and stripped of solvent by vacuum distillation.The residue is taken up in ethyl acetate. The ethyl acetate solution isconsecutively washed with water, aqueous 10 percent potassiumbicarbonate, water, ice-cold aqueous l0 percent ammonium sulfide,ice-cold aqueous l0 percent ammonium hydroxide, water, 5 percenthydrochloric acid, water, and aqueous 1 percent potassium bicarbonate.Solvent is then removed by vacuum distillation and the residuechromatographed on silica gel, using benzene and ethyl acetate asdeveloping solvents. From an eluate comprising 10 percent ethyl acetatein benzene, on evaporation of solvent and recrystallization of theresidue from ether, l7a-ethynyl-l7fihydroxyl 0,l7aB-dimethyl-D-homo-C-norl 3a-gonal ,4- dien-3-one is obtained as thehemi(diethyl etherate) melting at 181-183". Solvent of crystallizationis removed by heating in vacuo. The nonsolvated product has the formulaEXAMPLE 8 A. 3B-Formyloxyl 0, l 7afl-dimethyl-D-homo-C-nor-Sa,l3a-gonan-l7B-yl methyl ketone. A solution of 26 parts of 3B-hydroxylO, l 7afi-dimethyl-D-homo-C-nor-5a, l 3a-gonanl7B-yl methyl ketone inl80 parts of 98 percent formic acid is allowed to stand at roomtemperatures for l hour, then diluted with l0 volumes of water. Theprecipitate thrown down is filtered off and recrystallized from aqueousacetone to give 33- formyloxyl 0, l 7aB-dimethyl-D-homo-C-nor-5a, l3a-gonanl7fl-yl methyl ketone melting at 92-94 B l7B-Acetoxy-3B-formyloxyl 0, l 7aB-dimethyl-D-homo- C-nor-Sa, l 3a-gonaneA solution of 26 parts of 3B-formyloxyl0. l7aB-dimethyl-D-homo-C-nor-5a. l 3a-gonanl 7-yl methyl ketone and 10parts of m-chloroperoxybenzoic acid in 1070 parts of dichloromethane isallowed to stand at room temperatures for l week. Approximately 30 partsf calcium hydroxide is thereupon introduced and the resulting mixturethen stirred for 30 minutes. Insoluble solids are filtered off andsolvent removed from the filtrate by vacuum distillation. The residue isl7B-acetoxy-3B-forrnyloxyl 0, l 7aB-dimethyl-D-homo-C- nor-5a, l3a-gonane C. l7/3-Acetoxyl 0, l 7aB-dimethyl-D-homo-C-nor-Sa. l 30:-gonan-3B-ol. A solution of approximately 26 parts of I73-acetoxy-SB-formyloxyl 0, l 7afl-dimethyl-D-homo-C-nora,l3a-g'onane in440 parts of benzene is absorbed on 600 parts of alkaline alumina.Elution with a mixture of 50 percent ethyl acetate in benzene followedby removal of solvent from the eluate by vacuum distillation affordsl7/3-acetoxy-l0,l7 aB-dimethyl-D-homo-C-nor-5a,l 3a-gonan-3B-ol which,recrystallized from a mixture of acetone and hexane, melts at 9l-93 D.l7B-Acetoxy-l0,l7aB-dimethyl-D-homo-C-nor-5a,13agonan-3-one. To asolution of 135 parts of l7B-acetox l 7afi-dimethyl-D-homo-C-nor-5a, l3a-gonan-3B-ol in 2400 parts of acetone at 5 is added 27 parts ofchromium trioxide in a mixture of 39 parts of sulfuric acid and 150parts of water. After 15 minutes, 3000parts of water and 160 parts of 2-propanol are introduced. The resulting mixture is extracted withdichloromethane; and the extract is consecutively washed with water,aqueous potassium bicarbonate, and water. The extract is then dried overmagnesium sulfate and stripped of solvent by vacuum distillation. Theresidue is chromatographed on silica gel, using benzene and ethylacetate as developing solvents. From an eluate comprising percent ethylacetate in benzene, on evaporation of solvent, amorphous l7Bacetoxy-l0,1 7afi-dimethyl-D-homo-C-nor-5a ,l 3a-gonan-3-one is obtainedas the residue.

E. l 7B-Acetoxyl 0, l 7aB-dimetl1yl-D-homo-C-nor- 13agona-l,4-dien-3-one. Substitution of 33 parts of l7B-acetoxy-10,17aB-dimethyl'D-homo-C-nor-Sa,l3a-gonan-3-one for the l 7a-ethynyll7fi-hydroxyl 0, l 7aB-dimethyl-D-homo-C- nor-Sa,l3a-gonan-3-one calledfor in example 7C afiords, by a procedure identical with that describedtherein except that the product is isolated from an eluate comprising 5percent ethyl acetate in benzene and is recrystallized from a mixture ofacetone and hexane, l7B-acetoxy-l0, l7aB-dimethyl-D-homo-C-nor-l3a-gona-l,4-dien-3-one melting at 135-137". The product hasthe formula on, 000cm l 7fi-l-lydroxy-l0,l7aB-dimethy1-D-homo-C-nor-lZia-gonal,4-dien-3-one. A solution of 85 parts'of l7fi-acetoxy-l0,l7aB-dimethyl-D-homo-C-nor-l 3a-gona-l ,4-dien-3-one in 4000 parts ofmethanol and I090 parts of aqueous 10 percent potassium hydroxide isheated at the boiling point under reflux for 2 hours, whereupon methanolis removed by vacuum distillation and the residue diluted with an equalvolume of water. The resultant mixture is extracted withdichloromethane. The extract, stripped of solvent by vacuumdistillation, affords 17B- hydroxyl 0, l 7a/3-dimethyl-D-homo-C-nor-l3a-gonal ,4- dien-B-one as the residue which, recrystallized from amixture of ether and hexane, melts at l 25-l27. The product has theformula EXAMPLE 10 l 7B-Acetoxyl 0, l 7aB-dimethyl-D-homo-C-nor-l3a-gon-4- en-3-one. To a mixture of 630 parts of liquid ammonia at 70containing 3 parts of lithium is added 9 parts of l7fi-acetoxy- 10,17aB-dimethyl-D-homo-C-norl 3a-gonal ,4-dien-3-one in approximately 180parts of tetrahydrofuran. Approximately 200 parts of ammonium chlorideis introduced a moment later, whereupon the reaction mixture is allowedto stand (briefly) until the color disappears. Ammonia is then removedby distillation and the residue diluted with an equal volume of water.The resultant mixture is extracted with dichloromethane. The extract iswashed with water, dried over anhydrous sodium sulfate, and thereuponstripped of solvent by vacuum distillation. The residue is taken up inether, and the ether solution is dried over anhydrous sodium sulfate inthe presence of decolorizing charcoal. Upon evaporation of the solvent,l 7fi-acetoxy-10,17aB-dimethyl-D-homo-C-norl3a-gon-4-en-3-one isobtained as the residue. The product has the formula CH; H l CH Examplell 1 7fl-Acetoxyl 0, l 7aB-dimethyl-D-homo-C-nor-l Zia-gona-4,6-dien-3-one. To 60 parts of l7B-acetoxy-lOJ7aB-dimethyl-D-homo-C-nor-l 3a-gon-4-en-3-one in 78 parts of tert-butylalcohol is added 100 parts of chloranil. The resultant mixture isstirred at the boiling point under reflux in a nitrogen atmosphere forapproximately 5 hours, then cooled to room temperature and diluted with5 volumes of water. The mixture thus obtained is extracted withdichloromethane. The extract is washed successively with aqueous 5percent potassium hydroxide and water, whereupon solvent is removed byvacuum distillation and the residue chromatographed on silica gel, usingbenzene and ethyl acetate as developing solvents. From an eluatecomprising 5 percent ethyl acetate in benzene, on evaporation ofsolvent, l7B acetoxy-l0,l 7aB-dimethyl-D-homo-C-nor-l3a-gona-4,6-dien-3-one is obtained as the residue. Theproduct is amorphous. it has the formula -OCOCH3 H CH3 -OCOCH:

EXAMPLE l2 1 7B-Hydroxyl0, 1 7a.,8-dimethyl-D-homo-C-norl Zia-gona-4,6-dien-3-one. A solution of parts of l7B-acetoxy-l0,l7aB-dimethyl-D-homo-C-norl 3a-gona-4,6-dien-3-one in 4000 parts ofmethanol and I090 parts of aqueous 10 percent potassium hydroxide isheated at the boiling point under reflux for 2 hours, whereupon methanolis removed by vacuum distillation and the residue diluted with an equalvolume of water. The resultant mixture is extracted withdichloromethane. The extract is stripped of solvent by vacuumdistillation, affording l7B-hydroxyn l 0, l 7aB-dimethyl-D-homo-C-nor l3agonu-4,6- dien-3-one as the hemihydrate which, recrystallized fromaqueous acetone, melts at l64-l67. Water of crystallization is removedby heating in yacuo. The anhydrous product has the formula EXAMPLE l310,17aB-Dimethyl-D-homo-C-nor-l3agona-4,6-diene- 3,l7-dione. To amixture of 146 parts of l7/3-hydroxy-l0,l7 aB-dimethyl-D-homo-C-norl3a-gona-4,6-dien-3-one and 790 parts of acetone is slowly added 52 partsof chromium trioxide in a mixture of 85 parts of concentrated sulfuricacid with 150 parts of water. The resultant mixture is stirred atambient temperatures for approximately 20 minutes, whereupon it isdiluted with 320 parts of 2-propanol. The mixture thus obtained isextracted with dichloromethane. The extract is consecutively washed withwater and aqueous 1 percent potassium bicarbonate, then stripped ofsolvent by vacuum distillation. Recrystallization of the residue fromaqueous acetone affords l0,l 7aB-dimethyl-D-homo-C-norl3a-gona-4,6-diene- 3,l7-dione as the hemihydrate melting at l80l83.Water of crystallization is removed by heating in vacuo. The anhydrousproduct has the formula EXAMPLE l4 0Ha on H EXAMPLE 15 10, l7aB-Diniethyl-D-homo-Gnor-l 3a-gon-4-ene-3, l 7- dione. To a mixture of146 parts of l7B-hydroxy-l(),l7a/3-dimethyl-D-homo-C-nor-l3a-gona-4,6-dien-3-one and 790 parts of acetoneis slowly added 52 parts of chromium trioxide in a mixture of parts ofconcentrated sulfuric acid with parts of water. The resultant mixture isstirred at ambient temperatures for approximately 20 minutes, whereuponit is diluted with 320 parts of 2-propanol. The mixture thus obtained isextracted with dichloromethane. The extract is consecutively washed withwater and aqueous 1 percent potassium bicarbonate, then stripped ofsolvent by vacuum distillation. Recrystallization of the residue from amixture of dichloromethane and cyclohexane affords l0,l7aB-dimethyl-D-homo-C-norl 3a-gon-4-ene-3, l 7-dione melting at -1 68"lhe product hasthe formula E II n EXAMPLE 16 A. To 19 parts of 22a,5a-C-nor-D-hom0-l 8nor-spirostan- 3,8-ol-l7a-one" [J. Amer. Chem. Soc., 76, 4013 (1954)] in55 parts of ethylene glycol is added 50 parts of potassium hydroxide and50 parts of hydrazine hydrate. The resultant mixture is stirred andheated at the boiling point in a current of nitrogen until, after l/2hours, the temperature reaches where it is maintained by appropriateheating during continued stirring for 3 hours. The resultant solution iscooled and then precipitated by addition of water. The precipitate isfiltered out, washed with water, dried in air, and thereuponchromatographed on silica gel, using benzene and ethyl acetate asdeveloping solvents. From an eluate comprising l0 percent ethyl acetatein benzene, on evaporation of solvent and recrystallization of theresidue from ethyl acetate, a product melting at l74-l 77 is obtained.

B. 3fl-Hydroxyl O-methyl-D-homo-C-nor-Sa, l 3a-gonl 6- en-l7-yl methylketone. A mixture of 134 parts of the product of the foregoing example16A, 80 parts of acetic acid, and 95 parts of octanoic acid is heated to240 during 15 minutes, and thereafter at 240-250 for 20 minutes, whilevolatile components are allowed to distill. The resultant mixture iscooled and then successively diluted with 350 parts of ether, 200 partsof water, and excess aqueous 10 percent potassium hydroxide. The mixturethus obtained is stirred vigorously at room temperatures for 20 minutes,whereupon the nonaqueous phase is separated and consecutively washedwith water, aqueous 5 potassium hydroxide, and water, then stripped ofsolvent by vacuum distillation.

To 167 parts of the residue in a mixture of 1000 parts of acetic acidwith 1260 parts of 1,2-dichloroethane at --5 is added, during 20minutes, a solution of 90 parts of chromium trioxide in 800 parts ofaqueous 90 percent acetic acid. The resultant mixture is stirred for 1hour at 0, then diluted with a solution of 100 parts of sodium bisulfitein 400 parts of water, and thereafter with 1000 parts of water. Themixture thus obtained is extracted with ether. The ether extract iswashed with water and stripped of solvent by vacuum distillation,keeping the temperature below 60. The residue is taken up in ether, andthe ether solution is filtered. The filtrate is washed with aqueous 1percent potassium bicarbonate, dried over magnesium sulfate, andstripped of solvent by vacuum distillation.

A mixture of 174 parts of the residue, 600 parts of aqueous 20 percentpotassium hydroxide, and 1040 parts of tert-butyl alcohol is stirred atthe boiling point under reflux in a nitrogen atmosphere for 90 minutes,whereupon the alcohol is distilled off and the residue diluted withvolumes of water. The resultant mixture is extracted with ether. Theether extract is washed with water, dried over magnesium sulfate, andstripped of solvent by vacuum distillation. The residue ischromatographed on silica gel, using benzene and ethyl acetate asdeveloping solvents. From an eluate comprising percent ethyl acetate inbenzene, on evaporation of solvent and recrystallization of the residuefrom a mixture of acetone and hexane, 3 B-hydroxylO-methyl-D-homo-C-nor-Sa, l 3a-gon- 16-en-l7-yl methyl ketone melting atl44-l46 is obtained.

C. 3 B-Acetoxyl O-methyl-D-homo-C-nor-Sa, l 3a-gonl 6- en- 1 7-yl methylketone. A mixture of 1 part of 3B -hydroxy-l0- methyl-D-homo-C-nor-Sa, l3a-gonl 6enl 7-yl methyl ketone, 200 parts of pyridine, and 100 parts ofacetic anhydride is allowed to stand at room temperatures overnight,then diluted with 5 volumes of water. The resultant mixture is extractedwith dichloromethane. The extract is washed with aqueous 5 percentpotassium hydroxide, dried over magnesium sulfate, and stripped ofsolvent by vacuum distillation. The amorphous residue is3l3-acetoxy-IO-methyl-D-homo-C-nor- 501,1 3a-g0nl 6-en-l 7-yl methylketone.

D. 3B-Acetoxyl O-methyl-D-homo-C-nor-Sa, l 3a-gonanl7B-yl methyl ketoneoxime. A solution of parts of 3B- acetoxy-.l O-methyl-D-homo-C-nor-Sa, l3a-gonl 6-enl 7-yl methyl ketone and 16 parts of hydroxylaminehydrochloride in 400 parts of pyridine is allowed to stand at roomtemperatures overnight. Upon dilution with 5 volumes of water, aprecipitate is thrown down. The precipitate is filtered off, washed withwater, dried in air, and recrystallized from aqueous acetone to give3B-acetoxy-IO-methyl-D-homo-C-nor- 5a,l3a-gonan-l7B-yl methyl ketoneoxime melting at E. 3B-Hydroxy-l O-methyl-D-homo-C-nor-Sa, l3a-gonanl7-one. To a stirred solution of 6 parts of 3B-acetoxy-l0-methyl-D-homo-C-nor-Sa,13a-gonan-l7B-yl methyl ketone oxime in 100 partsof pyridine at 5 is added, during 15 minutes, a cold solution of 17parts of phosphorus oxychloride in 100 parts of pyridine. The resultantmixture is maintained at -5 for 2 hours, then slowly poured into 5volumes of cold water. The mixture thus obtained is stirred vigorouslyfor 25 minutes, then extracted with dichloromethane. The dichloromethaneextract is washed with aqueous 2 percent potassium hydroxide andstripped of solvent by vacuum distillation.

A solution of 3 parts of the residue in 400 parts of methanol and [2parts of concentrated hydrochloric acid is heated at the boiling pointunder reflux for 2 hours. Methanol is thereupon removed by vacuumdistillation, and the residue is diluted with 5 volumes of water. Theprecipitate which forms is filtered off, washed with water, dried inair, and recrystallized from aqueous acetone to give3B-hydroxy-l0-methyl-D- homo-C-nor-Sa, l 3a-gonanl 7-one melting at86-88".

F. l0-Methyl-3B-(tetrahydropyran-Z-yloxy)-D-homo-C-nor-5a,l3a-gonan-l7-one. A solution of 180 parts of 3B- hydroxylO-methyl-D-homo-C-nor-Sa, l 3a-gonan- 1 7-one in l760 parts of benzene,5 parts of toluenesulfonic acid, and 184 parts of dihydropyran isallowed to stand at room temperature for 1 hour, then successivelydiluted with 20 parts of pyridine and 5 volumes of water. The resultantmixture is extracted with benzene. The benzene extract is washed withwater and stripped of solvent by vacuum distillation. The residue islO-methyl-3fi-(tetrahydropyran-Z-yloxy)-D-homo- C-nor-Sa, l 3a-gonanl 7-one.

G. l0Methyl-3B-(tetrahydropyran-Z-yloxy)-D-homo-C- nor-5a,]3a-gonan-l7,801. To a stirred mixture of 640 parts of tert-butyl alcohol and l 120parts of liquid ammonia is added a solution of 20 parts ofl0-methyl-3/3-(tetrahydropyran-Z-yloxy)-D-homo-C-nor-5a,l3a-gonan-l7-one in 720 parts of tetrahydrofuran, followed by 6 parts oflithium wire. Stirring is continued for 2 hours, whereupon the ammoniais distilled and the residue diluted with 5 volumes of water. Theresultant mixture is extracted with benzene. The benzene extract iswashed with water and stripped of solvent by vacuum distillation to givel0-methyl-3B-(tetrahydropyran-Z-yloxy)-D-homo-C-nor- 501,1 3a-gonan-l73-01.

H. l7B-Benzoyloxy-lO-methyl-D-homo-C-nor-Sa,13agonan-3B-0l. A solutionof 20 parts of l0methyl-3B- (tetrahydropyran-2-yloxy-D-homo-C-nor-Sa, l3a-gonan- 1 7B- 0] in 200 parts of pyridine is heated at for 30 minuteswith 24 parts of benzoyl chloride. The resultant mixture is cooled andthen diluted with 30 parts of water. The mixture thus obtained is heatedat 90 for 30 minutes, then consecutively diluted with parts of water,1600 parts of methanol, and excess hydrochloric acid. This mixture, inturn, is stirred at room temperatures for 2 hours, neutralized withpotassium hydroxide, and concentrated to one-half volume by vacuumdistillation. The concentrate is extracted with dichloromethane. Thedichloromethane extract is washed with aqueous 2 percent potassiumhydroxide and stripped of solvent by vacuum distillation. The residue isl7/3-benzoyloxylO-methyl-D-homo-C-nor-Sa, l 3a-gonan-3B-ol.

l. l7/3-Benzoyloxyl O-methyl-D-homo-C-nor-5a,l 3agonan-3-one. To amixture of 146 parts of l7B-benzoyloxyl O-methyl-3B-(tetrahydropyran-Z-yloxy)-D-homo-C-nor- 5a,l3a-gonane and 790parts of acetone is slowly added 52 parts of chromium trioxide in amixture of 85 parts of concentrated sulfuric acid with 150 parts ofwater. The resultant mixture is stirred at ambient temperatures forapproximately 20 minutes, whereupon it is diluted with 320 parts of2-propanol. The mixture thus obtained is extracted with dichloromethane.

The dichloromethane extract is washed with water and stripped of solventby vacuum distillation. The residue is chromatographed on silica gel,using benzene and ethyl acetate as developing solvents. From an eluatecomprising 1 percent ethyl acetate in benzene, on evaporation ofsolvent, amorphous 17B-benzoyloxy- 1 O-methyl-D-homo-C-nor- 5a, 13a-gonan-3-one is obtained.

J. l7B-Benzoyloxyl O-methyl-D-homo-C-norl 3a-gona-l ,4 -dien-3-one. Amixture of 33 parts of l7B-benzoyloxy-l0-methyl-D-homo-C-nor-Sa,l3a-gonan-3-one and 20 parts of selenium dioxidein a mixture of 1200 parts of tert-butyl alcohol and 10 parts ofpyridine is heated at the boiling point under reflux in a nitrogenatmosphere for 65 hours. The red precipitate which forms is filtered offand washed with ethyl acetate. Filtrate and wash are combined andconcentrated to dryness by vacuum distillation. The residue is taken upin ethyl acetate. The ethyl acetate solution is consecutively washedwith water, aqueous l0 potassium bicarbonate, water, ice-cold 10 percentammonium sulfide, ice-cold 10 percent ammonium hydroxide, water, dilute5 percent hydrochloric acid, water, and aqueous 1 percent potassiumbicarbonate. Solvent is then removed by vacuum distillation, and theresidue is chromatographed on silica gel, using benzene and ethylacetate as developing solvents. From an eluate comprising 5 percentethyl acetate in benzene, on evaporation of solvent, 17B- benzoyloxylO-methyl-D-homo-C-nor- I Sa-gona-l ,4-dien-3- one is obtained as theresidue. The product has the formula nut-mu.

EXAMPLE 1? l 7B-Hydroxyl O-methyl-D-homo-C-norl 3a-gona-l ,4-dlcn-3-onc. A solution of 85 parts of l7B-benzoyloxy-l0-mothyl-D-homo-C-nunl Sa-gona-l ,4-dien-3-one in 4000 parts of methanoland I090 parts of aqueous l percent potassium hydroxide is heated at theboiling point under reflux for 2 hours, whereupon methanol is removed byvacuum distillation and the residue diluted with an equal volume ofwater. The resultant mixture is extracted with dichloromethane. Theextract, stripped of solvent by vacuum distillation, affordsl7B-hydroxy-lO-methyl-D-homo-C- nor-IBa-gona-l,4-diene-3-one as theresidue. The product has the formula i OH EXAMPLE l8lO-Methyl-D-homo-C-norl 3a-gona-l ,4-diene-3,l 7-dione. To a mixture of146 parts of l7/3-hydroxy-lO-methyl-D-homo- C-nor-l3agona-l,4-dien-3-oneand 790 parts of acetone is slowly added 52 parts of chromium trioxidein a mixture of 85 parts of concentrated sulfuric acid with 150 parts ofwater. The resultant mixture is stirred at room temperature forapproximately one-half hour, whereupon it is diluted with 400 parts of2-propan0l. The resultant mixture is extracted with dichloromethane. Theextract is consecutively washed with water and aqueous l percentpotassium bicarbonate, then stripped of solvent by vacuum distillation.The residue is 10- methyl-D-homo-C-norl 3a-gona-l ,4-diene-3, l 7-dione,having the formula EXAMPLE 19 A. l7B-Benzoyloxy-2a,4a-dibromolO-methyl-D-honio-C- nor-5a,]3a-gonan-3-one. To a solution of 96 parts of1713- benzoyloxyl O-methyl-D-homo-C-nor-Sa, 1 3a-gonan-3-one in 5000parts of acetic acid and 50 parts of a 30 percent solution of hydrogenbromide in acetic acid at is added, during 5 minutes, a solution of 80parts of bromine in 200 parts of acetic acid. The resultant mixture isallowed to stand at ambient temperatures for 2 hours, whereupon theprecipitate which forms is filtered off, washed with water, dried inair, and recrystallized from a mixture of dichloromethane and methanolto give l7B-benzoyloxy-2a,4a-dibromo-lO-methyl- D-homo-C-nor-5a,l3a-gonan-3-one.

B. l 7B-Benzoyloxyl O-methyl-D-homo-C-norl 3a-gon-4- en-3-one. To 260parts of acetone maintained at around 20 is added 34 parts of bromine.The resultant mixture is stirred until decolorized, at which point 100parts of potassium carbonate and 160 parts of acetone are introduced andstirring resumed for a further 30 minutes. Insoluble solids are filteredout and washed with acetone. To the combined filtrate and wash are added1740 parts of sodium iodide and l 120 parts of acetone. The mixture thusobtained is heated at the boiling point under reflux in an atmosphere ofnitrogen for 15 minutes, whereupon 3i parts ofl7/3-benzoyloxy-2a,4adibromo-lO-methyl-D-homo-C-nor-5a,l 3a-gonan-3-oneis introduced. The resultant mixture is heated at the boiling pointunder reflux in a nitrogen atmosphere for 2% hours, at which point 30parts of oxalic acid is added and boiling under reflux in nitrogenresumed for a further 1 hour. The mixture is then diluted with ethylacetate and filtered. The filtrate is consecutively washed with aqueousl percent potassium bicarbonate and water, and dried over magnesiumsulfate. A mixture of parts of acetic acid with 200 parts of zinc dustis added, and the resultant mixture is stirred for a total of 20 minutesduring which decolorization occurs. The mixture is then filtered; andthe filtrate is washed successively with water, aqueous 5 percentpotassium hydroxide, and water, then stripped of solvent by vacuumdistillation. The amorphous residue is l 7l3-benzoyloxyl 0-methyl-D-homo-C-nor-3 l a-gon-4-en-3- one, having the formula i i iEXAMPLEZO l7B-Hydroxyl O-methyl-D-homo-C-norl 3a-gon-4-en-3- one. Asolution of 85 parts of 17,8-benzoyloxy-l0 -methyl-D-homo-C-nor-l3a-gon-4-en-3-one in 4000 parts of methanol and i090 partsof aqueous 10 percent potassium hydroxide is heated at the boiling pointunder reflux for 2 hours, whereupon methanol is removed by vacuumdistillation and the residue diluted with an equal volume of water. Theresultant mixture is extracted with dichloromethane. The extract iswashed with water, dried over magnesium sulfate, and stripped of solventby vacuum distillation, affording 17B- hydroxyl O-methyl-D-homo-C-nor-l3a-gon-4-en-3-one as the residue which, recrystallized from a mixture ofacetone and hexane, melts at 1 14-1 16. The product has the formulaEXAMPLE 2i l7B-Hydroxyl Omethyl-D-homo-C-norl 3a-gon-4-ene- 3,l7-dione.To a mixture of M6 parts of l7B-hydroxy-l0-methyl-D-homo-C-nor-l3a-gon-4-en-3-one and 790 parts of acetone isslowly added 52 parts of chromium trioxide in a mixture of 85 parts ofconcentrated sulfuric acid with parts of water. The resultant mixture isstirred at room temperatures for approximately 20 minutes, whereupon itis diluted with 32 parts of Z-propanol. The mixture thus obtained isextracted with dichloromethane. The extract is consecutively washed withwater and aqueous potassium bicarbonate, then stripped of solvent byvacuum distillation, affording a residue which, recrystallized from amixture of acetone and hexane, melts at l34-l 36. The product thusobtained is 178- hydroxyl 0 methyl-D-homo-C-nor-l 3agon-4-ene-3,l7-dione1 developing solvents. From an eluate comprising percenttetartoacetonate, from which solvent of crystallization is wherein Rrepresents hydrogen or methyl; R represents removed by heating in vacuo.The nonsolvated product has hydrogen, lower alkanoyl, or benzoyl; and R"represents the formula hydrogen or methyl.

3. A compound according to claim 1 having the formula 5 ([JH; II I CH3/OR n E\ /5 o H H I EXAMPLE 22 0- IO-Methyl-D-homo-C-nor-l3agona-4,6-diene-3, l 7-dione. To 60 parts ofl7B-hydroxy-IO-methyl-D-homo-C-nor-l3agon-4-ene-3,17-dione in 78 partsof tert-butyl alcohol is added wherein re presents hydrogen, loweralkanoyl, or benzoyl 100 parts of chloraml. The resultant mixture ISheated, wlth and represents hydrogen or m ethyl Stirring at the boilingpoint under reflux a mogen 4. Acompound according to claim lwhich isl7B-hydroxymosphere for 5 hours. It is thereupon cooled to room tempera-I0,17a3 dimet hy1 D homo C nr l ture and diluted with water. The mixturethus obtained is ex- A compound according to claim 1 which is 17B hydrxytracted with dichloromethane. The extract is washed succes- 10,170,,7afitrimethyl D homo;c nor 13a gn 4 en3 ne sively with aqueous 5 Potassiumhydmxide and water 5. A compound according to claim 1 having the formulastripped of solvent by vacuum distillation. The residue ischromatographed on silica gel, using'benzene and ethyl acetate as ethylacetate in benzene, on evaporation of solvent, 10- Hmethyl-D'homo-C-nor-l3a-gona-4,6-diene-3,17-dione is obon, tained. Theproduct has the formula I =0 H 0: wherein R represents hydrogen ormethyl.

7. A compound according to claim 1 which is l0,l7afl- What is laimed i40 dimethyl-D-homo-C-nor-l 3a-gonal ,4 diene 3,l 7-dione. l. A compoundof the formula 8. A compound according to claim 1 having the formula R HI CH3 R l 2 n l O wherein the endocyclic dotted lines indicate that thecompounds are exclusively A, A, or A; R represents hydrogen or methyl;and Z represents carbonyl or radical wherein R represents hydrogen ormethyl; represents oflhe formula hydrogen, lower alkanoyl, or benzoyl;and R represents hydrogen, lower alkyl, or ethynyl.

\ 9. A compound according to claim 1 having the formula C FRI! CH3 inwhich R represents hydrogen, lower alkanoyl, or benzoyl CH I i and R"represents hydrogen, lower alkyl, or ethynyl. a 5 2. A compoundaccording to claim 1 having the formula I H R o f CH I 0R u n I! 1 f H Owherein R represents hydrogen or lower alkanoyl and R" w representshydrogen or methyl.

19 20 10. A compound according to claim 1 which is l7B-hydroxwherein Rrepresents hydrogen or methyl.y-10,17afi-dimethyl-D-homo-C-nor-l3agona-l,4-dien-3-one. 16. A compoundaccording to claim 1 which is 10,17afi- 11. A compound according toclaim 1 in which is 173-dimethyl-D-homo-C-nor-l3a-gona-4,6-diene-3,l7-dione.hydroxy-10,17a,l7aB-trimethyl-D-homo-C-nor-l 3a-gona 17. A compoundaccording to claim 1 having the formula 1 ,4-dien-3-one. 5

12 A compound according to claim 1 having the formula Ii wherein Rrepresents hydrogen or methyl. 0:

13. A compound according to claim 1 which is10,17afldimethyl-D-homo-C-nor-l 3a-gon-4-ene-3, l 7-dione.

14. A compound according to claim 1 which is l7fi-hydroxylO-methyl-D-homo-C-norl 3a-gon-4-ene-3, l 7 -dione.

l I 15 A compound accordmg to c arm 1 having the formula when"!represents y n or lower alkanoyl and R represents hydrogen or methyl.

R 18. A compound according to claim I which is l7fi-hydrox- CHy-l0,l7aB-dimethyl-D-homo-C-nor-l 3a-gona-4,6-dien-3-one.

3 :0 i t O i i CERTIFICATE OF CORRECTION Patent No. 5, 5 Dated November5: 97

Inventor(s) William F. Johns It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

Cover page, line 1 of title and column 1, line 1, "10,17ai3" should be10,1? 36 Abstract, line 1, "10,17aB" should be 10,17a6

Column 1, line 55, -alk yl" should be CO-lower alkyl Column 1, line 59,"17a beta/nor" should be 178. beta/nor Column 1, line 70, "does" shouldbe dose Column 2, lines 2A, 26 8c 28, insert an after "one", dione", and'one", respectively.

Column 2, formula,

II I should be Column 3, line 12, "C-nor 5oz,l5c1-" should be C-nor-Sa,13G

Column 5, line 58, "gonnan should be ---gonan RM PC4050 (169) uscoMM-Dc60376-P59 U 5v GOVERNMENT PRINYING OFFICE I969 D366-33 UNITED STATESPATENT OFFICE Page 2 of 4 CERTIFICATE OF CORRECTION patent o, 3,622,631Dated November 23, 1971 Inventor(s) William F. Johns It is certifiedthat error appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

Column 5, line ll, "acetoxy-lO,l7aB-" should be acetoxy- 10,1?(1, l'faB-Colmun 5, line 49, 5 percent potassium" should be 5 percent hydrochloricacid, water, and aqueous 1 percent potassium Column 5, line 56,d,17as15aona-" should be --o,l7a6- trimethyl-D-homoCnor-l3dgona- Column5, line 57, after "obtained." insert The product has the formula Column6, line 5 delete "The product".

Column 6, line 62, "a, l7af5trimethyl-" should be (1,l7&B trimethyl-Column 7, line 5, "l7d,l7a-trimethyl-" should be --l7a,l7aB- trimethyl--Column 7, line 6, "17B-trimethyl-D-homoC-nor-l3a,l'Ta| should bel7B-acetoxy-lO,l70,l7aB

Column 7, line 9, "a,l7aBl30L-gon-" should be --0L,l7aB-trimethyl-D-homo-C-norl5d-gon- Column 7, line 30, "d-l'faBl5OL-gon"should be 00,178.6- trimethylDhomo-C-norl3agon- Column 7, line 59, "asThe resultant solvents. should be as developing solvents.

Column 8, line 11, "10.17%" should be 10.17aB- M POWSO (10459) USCOMM-DCwaveee a U 5 GOVERNMENT PR|NY|NG OFFICE \95 O 36G 1J UNITED STATESPATENT OFFICE Page 5 CERTIFICATE OF CORRECTION Patent No. 5,622,651Dated November 23, 1971 Inventor(5) William F. Johns It is certifiedthat error appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

Column 8, formula H CH C CH

H Column 8, line 6 1, "-gonane" should be -gonane.- Column 8, line 68,"parts i calcium" should be parts of calcium Column 9, line 8, "91-93%."should be 91-95% Column 9, lines 10-11, "acetoxy-,-l7a6" should be--a.Ceb0Xylo, '0

Column 9, line 1%, "BOOOparts" should be 3000 parts Column 11, line 2,"l7B-hydroxynlO,l7aB-" should be 176- hydroxy-l0,l7a6

Column ll, line 2, "ljagona" should be l3a-gona Column ll, line 23,"lfiagona" should be ljon-gona Column 12, line 5, "lja-gonat,6-dien5one"should be lBOL-gOn- L-en-Z-one Column 12, line 60, "5" should be 5%Column 13, line 18, "16am" should be l6-en Column 14, line 9, "lOmethyl"should be lO-methyl QM PO195OUO'69' uscommoc 60376-P69 U 5. GOVERNMENTPR|NT1NG OFFICE 1 I959 0-555-334 UNITED STATES PATENT OFFICE Page of LlCERTIFICATE OF CORRECTION Patent No. 3, 3 Dated November 23, 1971Inventor(s) William F. Johns It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

Column 1 line 55, "1O potassium" should be 10 percent potassium Column15, line 50, "l5agona" should be l3oL-gona Column 16, line 19, "-3lcn-"should be -l3a- Column 16, line 75, "-10 methyl" should be -lO-methylColumn 16, line 75, "-l5agon-" should be -l5a-gon- Column 17, line 24,"5 potassium" should be 5 percent potassium Column 17, line 56, "orradical" should be or a radical -'1 Column 18, line 23, "4-en3one"should be L-en-B-one Column 18, line 24, "5." should be -6.-.

Column 18, line 57, "R'" should be R" Column 19, line 2, "lfiagona"should be lBOL-gona Column 19, line 5, "1 in which is" should be 1 whichis Signed and sealed this 8th day of May 1973.

(smL) Attest:

EDWARD PLFLETGHERJR. ROBERT GOTTSCHALK Attesting Officer Commissioner ofPatents USCOMM-DC seam-pen & U S GOVERNMENY FRINYVNG OFFICE I9590*]55'134

2. A compound according to claim 1 having the formula
 3. A compoundaccording to claim 1 having the formula
 4. A compound according to claim1 which is 17 Beta -hydroxy-10, 17a Beta -dimethyl-D-homo-C-nor-13 Alpha-gon-4-en-3-one.
 5. A compound according to claim 1 which is 17 Beta-hydroxy-10, 17 Alpha ,17a Beta -trimethyl-D-homo-C-nor-13 Alpha-gon-4-en3-one.
 5. A compound according to claim 1 having the formula 7.A compound according to claim 1 which is 10,17a Beta-dimethyl-D-homo-C-nor-13 Alpha -gona-1,4-diene-3,17-dione.
 8. Acompound according to claim 1 having the formula
 9. A compound accordingto claim 1 having the formula
 10. A compound according to claim 1 whichis 17 Beta -hydroxy-10,17a Beta -dimethyl-D-homo-C-nor-13 Alphagona-1,4-dien-3-one.
 11. A compound according to claim 1 in which is 17Beta -hydroxy-10,17 Alpha ,17a Beta -trimethyl-D-homo-C-nor-13 Alpha-gona-1,4-dien-3-one.
 12. A compound according to claim 1 having theformula
 13. A compound according to claim 1 which is 10,17a Beta-dimethyl-D-homo-C-nor-13 Alpha -gon-4-ene-3,17-dione.
 14. A compoundaccording to claim 1 which is 17 Beta -hydroxy-10-methyl-D-homo-C-nor-13Alpha -gon-4-ene-3,17 -dione.
 15. A compound according to claim 1 havingthe formula
 16. A compound according to claim 1 which is 10,17a Beta-dimethyl-D-homo-C-nor-13 Alpha -gona-4,6-diene-3,17-dione.
 17. Acompound according to claim 1 having the formula
 18. A compoundaccording to claim 1 which is 17 Beta -hydroxy-10,17a Beta-dimethyl-D-homo-C-nor-13 Alpha -gona-4,6-dien-3-one.